5-Hydroxy-PGI1 morpholinylamides

ABSTRACT

The present invention provides 5-hydroxy-PGI 1 , morpholinylamides, which are useful pharmacological agents. These analogs of prostaglandin I 1  are useful for the stimulation of mammalian smooth muscle tissues.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of Ser. No. 815,648, filedJuly 14, 1977, issued as U.S. Pat. No. 4,110,532 on Aug. 29, 1978.

The present invention relates to 5-hydroxy-PGI₁, morpholinylamides, theessential material constituting a disclosure thereof being herebyincorporated by reference from U.S. Pat. No. 4,110,532, issued Aug. 29,1978. In particular the present invention relates to morpholinylamidesof 5-hydroxy-PGI₁ corresponding to the various carboxylic acidsdisclosed and claimed in U.S. Pat. No. 4,110,532.

We claim:
 1. A prostacyclin analog of the formula ##STR1## wherein Z₂ is##STR2## wherein one of p or q is the integer zero or one and the otheris the integer zero;Wherein Z₁ is (1) --(CH₂)_(g) --CH₂ --CH₂ --, (2)--(ch₂)_(g) --CH₂ --CF₂ --, or (3) trans--(CH₂)_(g) --CH═CH--, wherein gis the integer one, 2, or 3 when q is zero and zero, one, or 2 when q isone; Wherein R₈ is hydrogen, hydroxy, or hydroxymethyl; Wherein Y₁ is(1) trans--CH═CH--, (2) cis--CH═CH--, (3) --ch₂ ch₂ --, (4)trans--CH═C(Hal)--, or (5) --C.tbd.C-- wherein Hal is chloro or bromo;Wherein M₁ is ##STR3## wherein R₅ is hydrogen or alkyl with one to 4carbon atoms, inclusive: Wherein L₁ is ##STR4## or a mixture of ##STR5##wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same ordifferent, with the proviso that one of R₃ and R₄ is fluoro only whenthe other is hydrogen or fluoro; wherein R₂₁ and R₂₂ are hydrogen, alkylof one to 12 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms,inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkylof one to 3 carbon atoms, inclusive, or phenyl substituted withhydroxycarbonyl or alkoxycarbonyl of one to 4 carbon atoms, inclusive;and wherein R₇ is (1) --(CH₂)₃ --CH₃, ##STR6## wherein h is the integerzero or one; s is the integer zero, one, 2, or 3; and T is chloro,fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, orwith the proviso that not more than two T's are other than alkyl.
 2. Aprostacyclin analog according to claim 1, wherein R₈ is hydroxymethyl.3. (5S)-11-Deoxy-11α-hydroxymethyl-5-hydroxy-6α-PGI₁, morpholinylamide,a prostacyclin analog according to claim
 2. 4. A prostacyclin analogaccording to claim 1, wherein R₈ is hydrogen. 5.(5S)-11-Deoxy-5-hydroxy-6α-PGI₁, morpholinylamide, a prostacyclin analogaccording to claim
 4. 6. A prostacyclin analog according to claim 1,wherein R₈ is hydroxy.
 7. A prostacyclin analog according to claim 6,wherein q is one.
 8. 7α-Homo-2-nor-(5S)-5-hydroxy-6α-PGI₁,morpholinylamide, a prostacyclin analog according to claim
 7. 9. Aprostacyclin analog according to claim 6, wherein p is one. 10.9-Hydroxymethyl-(5S)-5-hydroxy-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 9. 11. A prostacyclin analog according toclaim 6, wherein Z₂ is ##STR7##
 12. A prostacyclin analog according toclaim 6, wherein Z₂ is ##STR8##
 13. (5R)-5-Hydroxy-6β-PGI₁,morpholinylamide, a prostacyclin analog according to claim
 12. 14. Aprostacyclin analog according to claim 6, wherein Z₂ is ##STR9## 15.(5S)-5-Hydroxy-6α-PGI₁, morpholinylamide, a prostacyclin analogaccording to claim
 14. 16. (5S)-5-Hydroxy-15-methyl-6α-PGI₁,morpholinylamide, a prostacyclin analog according to claim
 14. 17.(5S)-5-Hydroxy-16,16-dimethyl-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 14. 18. A prostacyclin analog according toclaim 11, wherein Z₂ is ##STR10##
 19. A prostacyclin analog according toclaim 18, wherein Y₁ is cis--CH═CH--.
 20. (5R)-5-Hydroxy-cis-13-6α-PGI₁,morpholinylamide, a prostacyclin analog according to claim
 19. 21. Aprostacyclin analog according to claim 18, wherein Y₁ is --C.tbd.C--.22. (5R)-5-Hydroxy-13,14-didehydro-6α-PGI₁, morpholinylamide, aprostacyclin analog according to claim
 21. 23. A prostacyclin analogaccording to claim 18, wherein Y₁ is trans--CH═C(Hal)--. 24.(5R)-5-Hydroxy-14-chloro-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 23. 25. A prostacyclin analog according toclaim 18, wherein Y₁ is --CH₂ CH₂ --. 26.(5R)-5-Hydroxy-13,14-dihydro-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 25. 27. A prostacyclin analog according toclaim 18, wherein Y₁ is trans--CH═CH--.
 28. A prostacyclin analogaccording to claim 27, wherein Z₁ is --(CH₂)_(g) --CH₂ --CF₂ --. 29.2,2-Difluoro-(5R)-5-hydroxy-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 28. 30. A prostacyclin analog according toclaim 27, wherein Z₁ is trans--(CH₂)_(g) --CH═CH--. 31.trans-2,3-Didehydro-(5R)-5-hydroxy-6α-PGI₁, morpholinylamide, aprostacyclin analog according to claim
 30. 32. A prostacyclin analogaccording to claim 27, wherein Z₁ is --(CH₂)_(g) --CH₂ --CH₂ --.
 33. Aprostacyclin analog according to claim 32, wherein g is one.
 34. Aprostacyclin analog according to claim 33, wherein R₇ is ##STR11## 35.(5R)-5-Hydroxy-17-phenyl-18,19,20-trinor-6α-PGI₁, morpholinylamide, aprostacyclin analog according to claim
 34. 36. A prostacyclin analogaccording to claim 33, wherein R₇ is ##STR12## 37.(5R)-5-Hydroxy-16-phenoxy-17,18,19,20-tetranor-6α-PGI₁,morpholinylamide, a prostacyclin analog according to claim
 36. 38. Aprostacyclin analog according to claim 33, wherein R₇ is --(CH₂)₃ --CH₃.39. A prostacyclin analog according to claim 38, wherein R₅ is methyl.40. (5R)-5-Hydroxy-15-methyl-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 39. 41. A prostacyclin analog according toclaim 38, wherein R₅ is hydrogen.
 42. A prostacyclin analog according toclaim 41, wherein at least one of R₃ and R₄ is fluoro. 43.(5R)-5-Hydroxy-16,16-difluoro-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 42. 44. A prostacyclin analog according toclaim 41, wherein at least one of R₃ and R₄ is methyl. 45.(5R)-5-Hydroxy-16,16-dimethyl-6α-PGI₁, morpholinylamide, a prostacyclinanalog according to claim
 44. 46. A prostacyclin analog according toclaim 41, wherein R₃ and R₄ are both hydrogen. 47.(5R)-5-Hydroxy-6α-PGI₁, morpholinylamide, a prostacyclin analogaccording to claim 46.